The present invention relates to an advantageous process for preparing isochroman-3-ones.
Isochroman-3-one is of great interest as an intermediate in the synthesis of pharmaceuticals and crop protection agents.
WO 97/12864, for example discloses the use of isochroman-3-one as an intermediate in the preparation of fungicides and pesticides.
The quality of traditional chemical processes is usually defined by the space/time yield. In contrast, in catalytical chemical processes the catalytical turnover number ("TON", i.e. the value which states how frequently a catalyst particle is used in the reaction) and the catalytical turnover frequence ("TOF", i.e. the value which states how frequently a catalyst particle is used in one hour of the reaction) are usually employed as quality criteria. Compared with the space/time yield, TON and TOF give additional information over the quality of the catalyst employed in the reaction.
Various processes for preparing isochroman-3-one are known from the literature. Thus, Yamamoto describes, in Tetrahedron Lett. 1997, Vol. 38, 3747 to 3750, a synthesis of isochroman-3-one by reacting 1,2-bishydroxymethyl-benzene and carbon monoxide in the presence of 1 mol % of a palladium catalyst and 10 mol % of hydrogen iodide. At 90.degree. C. and a carbon monoxide pressure of 9 MPa in acetone/water as solvent, isochroman-3-one is isolated in a yield of 56% after a reaction time of 42 hours.
Disadvantages of this process which may be mentioned are the presence of the highly corrosive hydrogen iodide and the relatively long reaction time.
In J. Am. Chem. Soc. 1980, Vol. 102, 4193 to 4198, Stille describes the synthesis of isochroman-3-one by reaction of ortho-bromomethylbenzyl alcohol, carbon monoxide and potassium carbonate in the presence of 1.6 mol % of a palladium catalyst and a drop of hydrazine in tetrahydrofuran as solvent. After 24 hours at 25.degree. C. and a carbon monoxide pressure of 0.1 MPa, isochroman-3-one is isolated in a yield of 71%.
It is a disadvantage that the ortho-bromomethylbenzyl alcohol, which is required as starting material, is not easily obtainable. In addition, the use of potassium carbonate impedes a simple practice of the process (release of CO.sub.2). Furthermore, a relatively long reaction time has to be taken into account.
WO 97/00850 A1 discloses a two-step process for preparing isochroman-3-one derivatives where initially a 1,2-bishalomethylbenzene derivative of the general formula (A) ##STR2## in which R is H, a halogen, a C.sub.1 -C.sub.6 -alkyl or a C.sub.1 -C.sub.6 -alkoxy radical and X is halogen, carbon monoxide and water are reacted in the presence of a hydrogen halide binder and a catalyst in an organic solvent, and the intermediate salt of the ortho-hydroxymethylphenylacetic acid of the general formula (B) in which M is an alkali metal or alkaline earth metal and n is 1 or 2 ##STR3## is subsequently treated with an acid and converted into the corresponding isochroman-3-one. Suitable catalysts are palladium, cobalt and iron catalysts. Suitable hydrogen halide binders are bases, in particular inorganic bases, for example calcium hydroxide. The acid used in the second reaction step of this process to bring about conversion of the salt of the ortho-hydroxymethylphenylacetic acid derivatives of the formula (B) into the corresponding isochroman-3-one is, for example, hydrochloric acid. The maximum TOF is 153.times.h.sup.-1 ; TON=153; yield 76.7% (cf. working example 4). The maximum TON is 170 (TOF=24.times.h.sup.-1); yield 84.7% (cf. working example 17).
According to this process, it is possible to obtain a yield of up to 87.4% of isochroman-3-one, but a relatively small amount of 8.75 g of .alpha.,.alpha.'-ortho-xylylene dichloride (1,2-bischloromethylbenzene) is reacted in not less than 100 g of tertbutanol. For further work-up, the reaction mixture is admixed with water, insoluble solids are separated off by filtration and the mixture is repeatedly extracted with ether. After acidification with concentrated hydrochloric acid, the mixture is once more extracted with ether, and isochroman-3-one is obtained from the collected ether fractions (TON=87; TOF=4.2.times.h.sup.-1 ; cf. also working example 5).
Owing to bases being used in the first step of the process and acidification in the second step, not less than 3 equivalents of monovalent salt are formed per equivalent of isochroman-3-one. Disadvantages of this process are, on the one hand, the use of large amounts of solvent and the formation of great amounts of salt and, on the other hand, the fact that it is a two-step process, and the numerous purification and extraction steps and the repeated use of ether as extractant.